Volume 27 Issue 10, October 2017: 1243-1257 | Open Access
ORIGINAL ARTICLES
5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers
Wenshuai Li1,*, Xu Zhang2,*, Xingyu Lu3,4,*, Lei You5,*, Yanqun Song4, Zhongguang Luo1, Jun Zhang1, Ji Nie3, Wanwei Zheng1, Diannan Xu1, Yaping Wang6, Yuanqiang Dong6, Shulin Yu7, Jun Hong6, Jianping Shi8, Hankun Hao6, Fen Luo6, Luchun Hua6, Peng Wang7, Xiaoping Qian9, Fang Yuan10,11, Lianhuan Wei11, Ming Cui5, Taiping Zhang5, Quan Liao5, Menghua Dai5, Ziwen Liu5, Ge Chen5, Katherine Meckel12, Sarbani Adhikari12, Guifang Jia11,13, Marc B Bissonnette12, Xinxiang Zhang10,11, Yupei Zhao5, Wei Zhang14, Chuan He3,10 and Jie Liu1,15
1Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China;
2Section of Hematology/Oncology, Department of Medicine, University of Illinois, Chicago, IL 60612, USA;
3Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA;
4Shanghai Epican Genetech, Co. Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China;
5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China;
6Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China;
7Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China;
8Department of Digestive Diseases, Pudong Hospital, Fudan University, Shanghai 201399, China;
9Department of Oncology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China;
10Beijing National Laboratory for Molecular Sciences, College of Chemistry, Peking University, Beijing 100871, China;
11Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China;
12Department of Medicine, The University of Chicago, Chicago, IL 60637, USA;
13Department of Chemical Biology, Structure and Function Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China;
14Department of Preventive Medicine and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
15Department of Immunology, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
Correspondence: Chuan He, E-mail: chuanhe@uchicago.edu; Jie Liu, E-mail: jieliu@fudan.edu.cn; Wei Zhang,(wei.zhang1@northwestern.edu)
DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.
10.1038/cr.2017.121
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